A Novel Randomized Trial Protocol for Evaluating Wound Healing Interventions.

Background: Randomized controlled trials using complete healing as an endpoint suffer from poor statistical power, owing to the heterogeneity of wounds and their healing trajectories. The Food and Drug Administration (FDA) has recently consulted with expert groups to consider percentage area reduction (PAR) of the wound over a 4-week period as a valid intermediate endpoint, creating the opportunity for more powerful study designs. Methods: A within-subject controlled study design comparing the PAR of venous leg ulcers (VLU) in patients over 4 weeks receiving different interventions. Twenty-nine patients received multilayer compression over 4 weeks, followed by neuromuscular electrostimulation (NMES) of the leg muscle pump in addition to compression for a further 4 weeks. Paired comparison was then made of PAR between the two phases. A second cohort of 22 patients received only multilayer compression throughout both 4-week phases. Results: Patients randomized to NMES saw a significant increase in healing rate compared with compression alone, whereas patients receiving compression only saw no significant change in healing rate throughout the course of the study. Conclusions: Intermittent NMES of the common peroneal nerve significantly accelerates the healing of VLU. It is well tolerated by patients and deserves serious consideration as an adjuvant to compression therapy. PAR is a useful metric for comparing the performance of wound healing interventions, and the self-controlled trial design allows sensitive discrimination with a relatively small number of subjects over a reasonably short trial period. The study is reported according to the CONSORT reporting guidelines. Clinical Trial Registration: NCT03396731 (ClinicalTrials.gov).

The impact of a new intervention for venous leg ulcers: A within-patient controlled trial.

A major obstacle to the development of new treatments for venous leg ulcers is the difficulty in generating evidence for their effectiveness. Randomised controlled trials using complete healing as the endpoint are seldom powered to be successful, owing to the heterogeneity of cohorts. A novel approach to the evaluation of treatments is presented, using a self-controlled trial model and two metrics of short-term healing rate as alternate endpoints: rate of wound margin advance, and percentage area reduction over 4 weeks. Two different treatment regimens are compared: multi-layer compression alone, versus multi-layer compression combined with activation of the venous leg pump by neuromuscular stimulation. With 60 patients, adding neuromuscular stimulation to multilayer compression resulted in a significant two-fold increase in the rate of wound healing over a 4-week period, both in terms of wound margin advance and in terms of percentage area reduction. The use of these short-term intermediate endpoint metrics together with a self-controlled study design offers potential for distinguishing between the relative efficacies of interventions more rapidly, with greater sensitivity, and with fewer subjects than a conventional RCT cohort model.

Measuring progress to healing: A challenge and an opportunity.

Complete healing is problematic as an endpoint for evaluating interventions for wound healing. The great heterogeneity of wounds makes it difficult to match groups, and this is only possible with multivariate stratification and/or very large numbers of subjects. The substantial time taken for wounds to heal necessitates a very lengthy study. Consequently, high quality randomised controlled trials demonstrating an effect of an intervention to a satisfactory level of statistical significance and with a satisfactory level of generalisability are extremely rare. This study determines that the healing of venous leg ulcers receiving multi-component compression bandaging follows a linear trajectory over a 4-week period, as measured by gross area healed, percentage area healed, and advance of the wound margin. The linear trajectories of these surrogates make it possible to identify an acceleration in healing resulting from an intervention, and allows self-controlled or crossover designs with attendant advantages of statistical power and speed. Of the metrics investigated, wound margin advance was the most linear, and was also independent of initial ulcer size.